Many drugs or toxicants are known to produce toxic effects associated with impairment of endocrine function and alteration of tissue content of cytochrome P-450, a hemoprotein which mediates steroid hydroxylations. Some examples are cadmium, diethylstilbestrol, spironolactone and various chlorinated hydrocarbons such as (2,2-bis(2-chlorophenyl-4-chloropheynl)1, 1-dichloroethane (o,p'-DDD) and dieldrin. Studies have been conducted with 2,3,7,8-tetachlorodibenzo-p-dioxin (TCDD), an environmental contaminant of chlorophenols and phenoxyacetic acids, which is associated with adverse effects in man such as acne, hirsutism and loss of libido. Preliminary studies have shown that TCDD depresses guinea pig testicular microsomal cytochrome P-450 content but does not alter rate of breakdown of this cytochrome. A possible explanation for some of the adverse effects associated with poisoning by TCDD and the other drugs or toxicants such as those mentioned is alteration of heme biosynthesis in various endocrine tissues. The goal of the research proposed for this project is to elucidate which enzymatic step(s) of the heme biosynthetic pathway in testis is impaired by TCDD. These studies will be extended to other toxicants such as those listed, and also to other endocrine tissues, such as the adrenal, ovary, placenta and thyroid gland. Knowledge of the enzymatic reactions altered by TCDD or other toxicants will facilitate testing of known inducers or inhibitors of these reactions in order to antagonize the effect of the toxic agent and provide treatment for poisoning episodes.